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Assessing the role of LRRTMs in synapse development and function

University of British Columbia

The leucine rich repeat transmembrane neuronal (LRRTM) proteins are a family of four synaptogenic cell adhesion molecules that instruct excitatory presynaptic differentiation and mediate postsynaptic differentiation. LRRTM1 and LRRTM2 are most potent at inducing presynaptic differentiation and have been shown to interact with neurexins at glutamatergic synapses. LRRTM4 has been recently identified as a major component of native AMPA-type glutamate receptor complexes, and is expressed at very high levels in dentate gyrus granule cells. Similar to neurexins, neuroligins, and several other synapse organizing proteins, LRRTMs are linked to psychiatric disorders such as autism spectrum disorders. LRRTM4 is also linked to risk of attempted suicide in females based on a recent genome-wide association study of over 2500 patients with bipolar disorder. Our project on LRRTM1 and LRRTM2 involved determining the role of these proteins in synapse development and function using LRRTM1 and 2 double knockout mice. Our results indicated that LRRTM1 and 2 are essential for normal excitatory synapse development and function in CA1 region but not the dentate gyrus. Our project on LRRTM4 assessed the role of this protein in synapse development. Using targeted deletion in mice, our results revealed that LRRTM4 is essential for normal excitatory synapse development and function in dentate gyrus granule cells but not in CA1 hippocampal pyramidal neurons. In addition, it was shown that LRRTM4 differentiates from LRRTM1 and 2 in terms of binding partners as it binds heparan sulfate proteoglycans (HSPGs). Experiments indicated that HSPGs are essential to mediate the synaptogenic activity of LRRTM4. Overall, our results from LRRTM1 and 2 and LRRTM4 projects indicate that members of the LRRTM family function in a cell-type specific manner through different presynaptic molecular pathways. This emphasizes the complexity of synapse-organizing protein networks and the importance of studying region specific roles of these synaptic proteins.

Text

2015-10-31

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/46530

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/